Uteroferrin is a purple colored, progesterone-induced glycoprotein containing two molecules of iron which is secreted by uterine endometrial epithelium of pigs (F. W. Bazer and R. M. Roberts, J. Exp. Zool., 228:373, 1983; R. M. Roberts and F. W. Bazer, Bio Essays, 1:8, 1984). Uteroferrin exists as a 35,000 Mr polypeptide having a purple color and as a heterodimer (Mr=80,000) with one of three "uteroferrin-associated proteins" which have high amino acid sequence homology with serine protease inhibitors (M. K. Murray, et al., J. Biol. Chem., 264:4143, 1989). The heterodimer has a rose color, but the biochemical and biological significance of the rose-form of uteroferrin and the uteroferrin-associated proteins is not known. Uteroferrin carries high mannose carbohydrate with the mannose-6-PO.sub.4 recognition marker for lysosomal enzymes (G. A. Baumbach, et al., Proc. Nat. Acad. Sci., U.S.A., 81:2985, 1984) and has acid phosphatase activity (D. C. Schlosnagle, et al, J. Biol. Chem. 249:7574, 1974). During pregnancy, uteroferrin is transported from uterine secretions into the fetal-placental circulation by specialized placental structures called areolae (R. H. Renegar, et al., Biol. Reprod., 27:1247, 1982). The mannose residues on uteroferrin are responsible for uteroferrin being targeted to reticuloendothelial cells of the fetal liver, the major site of hematopoiesis in fetal pigs (P. T. K. Saunders, et al., J. Biol. Chem., 260:3658, 1985).
Administration of radiolabelled iron to pigs results in endometrial secretion of uteroferrin carrying radiolabelled iron and incorporation of radiolabelled iron into fetal erythrocytes and cells of liver, spleen and bene marrow (C. A. Ducsay, et al., Biol. Reprod., 26:729, 1982; C. A. Ducsay, et al., J. Anim. Sci., 59:1303, 1984). Uteroferrin gives up its iron to fetal transferrin in allantoic fluid with a half-life of 12 to 24 hours (W. C. Buhi, et al, J. Biol. Chem., 257:1712, 1982). Further, administration of iron dextran to pregnant pigs on days 50, 60 and 70 (term is at 115 days), the period of maximum secretion of uteroferrin by the endometrium, results in a 20% increase in iron stores in neonatal piglets (C. A. Ducsay, et al., Biol. Reprod., 26:729, 1982; C. A. Ducsay, et al., J. Anim. Sci., 59:1303, 1984). These results suggest a role for uteroferrin in transplacental transport of iron. However, after Day 75 of gestation, translation of mRNA for uteroferrin decreases rapidly (R. C. M. Simmen, et al., Mol. Endocrinol. 2:253, 1988), secretion of uteroferrin by endometrial explant cultures declines (S. M. M. Basha, et al., Biol. Reprod., 20:431, 1979), and the amount of uteroferrin in allantoic fluid decreases dramatically (F. W. Bazer, et al., J. Anim. Sci., 41:1112, 1975). This suggests that an alternate mechanism for transplacental iron transport becomes operative between Days 75 and term when fetal/placental demands for iron are increasing (C. A. Ducsay, et al., Biol. Reprod., 26:729, 1982; C. A. Ducsay, et al., J. Anim. Sci., 59:1303, 1984).
Uteroferrin from pig uterus is a tartrate-resistant acid phosphatase with many properties in common with the Type 5 acid phosphatase in human placenta (C. M. Ketcham, et al., J. Biol. Chem., 260:5768, 1986), chondrocytes of humans with osteoclastic bone tumors and spleens of humans with hairy cell leukemia, Gaucher's disease and Hodgkin's disease. In addition, uteroferrin has characteristics similar to those for purple acid phosphatases from bovine, rat, mouse, and pig spleen, as well as bovine milk, bovine uterine secretions, equine uterine secretions, and rat bone (C. M. Ketcham, et al., J. Biol. Chem. 260:5768, 1985).
In the medical community there has long been a recognition of various disorders involving the hematopoietic system. These disorders include the anemias; myeloproliferative diseases; primary bone marrow dysfunctions, especially those involving pancytopenia; and the leukemias.
Depending on the nature of the hematopoietic disorder, various therapies may be used. Unfortunately, for many of these disorders, no adequate therapeutic approach is available and treatment consists primarily of basic management of the patient. Alternatively, where therapeutic agents are available, there are often significant toxic side effects associated with their use.
In order to circumvent the toxic side effects often associated with traditional chemotherapy, in recent years considerable research has focused on the discovery and use of "natural" hematopoietic growth factors, such as erythropoietin, or bone marrow transplants, as alternative forms of therapy. Although these modalities appear promising, they also have their limitations. For example, the use of bone marrow transplants has been severely limited due to the extreme difficulty in obtaining bone marrow which is histocompatible with the recipient. As a result, there continues to be considerable need for other agents capable of stimulating cells of the hematopoietic system.